Boosting Drug Discovery for Parkinson’s: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles

Abstract

The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 ± 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC/D3 cells was also observed, and their permeation across Caco-2 and hCMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls.

Prevention of Hypercholesterolemia with “Liposomes in Microspheres” Composite Carriers: A Promising Approach for Intestinal-Targeted Oral Delivery of Astaxanthin

“…Predicting the performance of drug delivery systems in the gut microenvironment sometimes requires the use of in vitro models . Caco-2 cells, in particular, are highly important for predicting drug absorption in humans, especially in the small intestine . Nevertheless, the verification of focused transportation mechanisms depends on the particular expression of FcRn by cells in the intestines.…”

“…41 Caco-2 cells, in particular, are highly important for predicting drug absorption in humans, especially in the small intestine. 42 Nevertheless, the verification of focused transportation mechanisms depends on the particular expression of FcRn by cells in the intestines. HepG2 was selected as a positive control due to its expression of FcRn.…”

Mechanistic Insights and Therapeutic Delivery through Micro/Nanobubble-Assisted Ultrasound

“…As a common progressive neurodegenerative disease, Parkinson’s disease (PD) is characterized by Lewy bodies formatted in alpha-synuclein-dominated neurons, which are caused by the death of dopaminergic neurons in the substantia nigra pars compacta of the midbrain [ 122 ]. Although the main treatment method is to supplement the endogenous source of dopamine, it cannot prevent continuous neuronal degeneration and may ultimately lead to recurrence [ 123 ]. Since the combination of micro/nanobubbles with transcranial low-intensity focus US can overcome the BBB, a micro/nanobubble-assisted ultrasound strategy is widely developing as a promising strategy to treat PD [ 124 ].…”

Artificial intelligence and machine learning‐aided drug discovery in central nervous system diseases: State‐of‐the‐arts and future directions

“…PD is a prime example of a multifaceted disease, including a broad range of motor and non‐motor symptoms and possible contribution of genetic and environmental risk factors 391 . Currently, there is no treatment to prevent the progressive depletion of dopaminergic neurons in the substantia nigra that underlies the movement control and cognitive loss, which is manifested with tremors and memory loss 392,393 . Available drug treatments are based on the administration of levodopa ( l ‐dopa) and catechol‐O‐methyltransferase or monoamine oxidase B inhibitors, offering only symptomatic relief to the patients 392 …”